Drug delivery systems have been increasingly applied to treatment of various diseases as ideal drug application forms. Of these, developments for improving circulation in blood by modifying drugs with polyethylene glycol have been widely performed and drugs obtained by modifying cytokines such as interferon and GCSF with polyethylene glycol have been placed on the market and have been widely used.
In general, as elimination paths of a drug applied into the body, there may be mentioned filtration excretion from kidney glomeruli and treatment by a reticuloendothelial system (RES system) represented by Kupper cell. Since the glomeruli function as a size-dependent filtration membrane, the filtration excretion path can be avoided by modifying the drug with a polyoxyalkylene to enlarge the size. Also, in the RES system, the drug is phagocytized by RES recognition through non-specific interaction (opsonization) but the polyoxyalkylene-modified compound exhibits a low interaction with a living body component, so that the RES recognition can be avoided. For such reasons, polyoxyalkylene derivatives have been widely used as DDS materials for elongating the circulation in blood.
Hitherto, as the polyoxyalkylene derivatives, a type of the derivatives having one reactive functional group at a terminal end of methoxypolyethylene glycol is common but recently, there has been developed a hetero polyfunctional polyoxyalkylene derivative having different reactive functional groups at both terminal ends and a polyoxyalkylene derivative having two proximate reactive functional groups (M. J. Roberts et al./Chemistry for peptide and protein PEGylation/Advanced Drug Delivery Reviews 54 (2002) 459-476). Since such derivative has two functional groups in proximate positions, it has effects that a metal atom is chelated, it acts as a pseudoantibody through bonding of an antibody fragment to each functional group, and an amount of a low-molecular-weight drug bonded can be increased. Moreover, since different reactive functional groups are present at both terminal ends, it is possible to introduce different molecules, for example, biofunctional molecules such as drug physiologically active substances and target-directing substances into individual terminal ends and thus the derivative has been used as a hetero crosslinker that crosslinks the biofunctional molecules each other or the biofunctional molecule and various drug carriers or devices.
Patent Document 1 discloses a structure wherein a branched chain and a drug are introduced into both terminal ends of polyethylene glycol via an amide bond. It is known that the circulation in blood, which is a characteristic of a polyoxyalkylene-modified compound, is improved as the molecular weight increases. On the other hand, when the molecular weight reaches a level of several tens of thousands, there is a problem that viscosity of a drug solution increases and drug design becomes difficult.
Patent Documents 2 and 3 disclose compounds obtained by activating a methoxypolyethylene glycol terminal end, subsequently reacting the terminal end with an amino group-containing core skeleton compound such as 1,3-diaminopropanol to introduce a polyethylene glycol chain via a urethane bond, and then introducing a plurality of functional groups into remaining hydroxyl groups.
Similarly, Patent Document 4 also discloses compounds obtained by activating a methoxypolyethylene glycol terminal end, subsequently reacting the terminal end with 2,3-diaminosuccinic acid protected with Boc group to introduce a polyethylene glycol chain via an amide bond, and then introducing a plurality of functional groups into remaining functional groups.
In the derivatives disclosed therein, a polyoxyalkylene chain and a core skeleton compound such as lysine are bonded via an amide bond, a carbamate bond, or an ester bond, but there is a problem that these bonds are liable to undergo hydrolysis during storage or during a reaction under alkaline conditions and, as a result, the polyoxyalkylene chain is dissociated.
Moreover, in the production thereof, since the production is performed via a step of reacting the core skeleton compound such as lysine with a reactive polyoxyalkylene derivative, there is a problem that impurities different in the introduced number of polyoxyalkylene chains are formed. It is industrially difficult to purify such polymeric compounds one another.
Furthermore, in each of the compounds disclosed in Patent Documents 2, 3 and 4, an asymmetric carbon is present in the core skeleton and there is a problem that the compound is not homogeneous when bonding to a drug and development to a medicament are considered.
Additionally, in the disclosed compounds, it is difficult to introduce different molecules, for example, biofunctional molecules such as drug physiologically active substances and target-directing substances into activated functional groups and thus it is difficult to further enhance the function of a polyethylene glycol-bonded compound.
Based on such background, there has been required a branched hetero polyfunctional polyoxyalkylene compound which has a high stability and facilitates achievement of homogeneity owing to the absence of an asymmetric carbon in the molecule.